PROJECT SUMMARY Relapse remains the most persistent and significant problem in drug abuse treatment. As many as 90% of smokers who attempt to quit eventually relapse, and smokers remain at high risk for relapse well after their acute withdrawal symptoms have subsided. Animal and human studies have revealed that drug-seeking responses and craving induced by conditioned stimuli (`cues') gradually increase in magnitude with long duration of abstinence, a phenomenon known as incubation. We have recently found that this phenomenon occurs in human smokers: a peak of reactivity to smoking cues occurs at one-month of abstinence, whereas shorter withdrawal was associated with moderate reactivity to smoking cues. It has been proposed that the dopaminergic system is involved in drug-seeking and craving, however no measure of dopamine transmission in the context of incubation of craving has been performed yet in humans. Imaging with positron emission tomography (PET) permits the measurement of neurochemicals in vivo. PET has become a powerful tool for neuroscientists to visualize and localize receptors and estimate the endogenous levels of neurotransmitters. The process of imaging requires the injection of a positron-emitting radiotracer (e.g. [11C]-(+)-PHNO) that binds to the protein of interest (e.g. dopamine receptors) followed by the measurement of this binding using the PET scanner. This method has been used to measure dopamine level fluctuations in humans. Our long-term objective is to understand the mechanisms of craving allowing developing strategies to prevent relapse. Our specific aims are to measure the effect of tobacco cue presentation on the [11C]-(+)-PHNO binding in human brain at five weeks of abstinence maintained with monetary incentives; comparison with neutral cue presentation. We will measure cravings and withdrawal and correlate these changes with the effects noticed on [11C]-(+)-PHNO binding in human brain. These studies will allow translating the basic science discoveries into clinical validation. Our long-term goal will be to use this novel paradigm to improve treatment approaches for smoking.